The main goal of this proposal is to design novel treatments for prostate cancer (PCa) that employ specific targeting of curcumin and genistein nanocomplexes to PCa cells. Prostate cancer is the third leading cause of death among men in America. While androgen deprivation has been found to be effective in treating androgen-dependent PCa, it is ineffective in treating advanced PCas which are the major cause of mortality. Recently, the natural products curcumin and genistein have demonstrated anti-inflammatory and anticancer effects in clinical studies, but their potential use for PCa prevention or treatment has been severely limited due to their poor bioavailability. Consequently, increasing solubility and bioavailability and targeted delivery of these products to specific cancer cells has been considered as the most promising strategy for these nontoxic natural products. Transgenex Nanobiotech, Inc. has developed novel nanoparticles for targeted delivery of small molecules such as curcumin and genistein that increase their solubility and stability. Chitosan-cyclodextrin-curcumin (3C) complexes significantly increase curcumin's half-life in biological media with serum. These results have led to the hypothesis that multifunctional 3C nanoparticles further complexed with genistein (3CG) can be delivered to the prostate to inhibit PCa progression and/or metastasis. The choice of curcumin and genistein as anti-PCa agents is based on their complementary effects in terms of bioavailability and synergistic actions in regulating gene expression and signaling, and inhibition of the growth of cancer cells. To test this hypothesis, we will conduct in vivo bioavailability and prostate-specific target ability studies for 3CG nanocomplexes in the first aim. Groups of mice will be given curcumin and genistein separately or together, either alone or in nanocomplxes. The drugs and complexes will be administered intraperitoneally or orally and the bioavailability of curcumin and genistein in the serum will be determined by HPLC. It is also planned to examine the potential of prostate cell specific delivery of 3CG nanoparticles coupled to peptide or antibodies against prostate stem cell antigen (PSCA). The results of Aim 1 will define the most effective route of delivery of 3CG-nanocompleses that will provide increased bioavailability and method for targeting nanoparticles to PCa tumors. In the second aim, it is planned to evaluate the antitumor efficacy of 3CG nanocomplexes delivered specifically to the prostate in TRAMP mice. All the methods and reagents needed for the study are available. Successful targeting of these nanocomplexes with improved bioavailability of the natural antitumor agents with proven safety records is expected to lead to new therapeutics for PCa and other cancers. PUBLIC HEALTH RELEVANCE: The main goal of this proposal is to design novel treatments for prostate cancer (PCa), the third leading cause of death among men in America, that employ specific targeting of curcumin and genistein nanocomplexes to PCa cells. Despite their proven safety record, neither curcumin nor genistein have been tested clinically because of their poor bioavailability. The proposed novel formulation is expected to eliminate the problem of bioavailability and to target the antitumor nanoparticles to prostate cancer cells thereby inhibiting their progression and/or metastasis.